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Teriparatide/denosumab superior to monotherapy for increased BMD
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Results from a randomized controlled trial suggest that combination denosumab and teriparatide was superior to either agent alone at increasing bone mineral density and led to greater improvements than previously reported with any other treatments approved for osteoporosis.
Twelve months after randomization, increases in posterior-anterior lumbar spine BMD were higher in the combination group (9.1%) compared with the teriparatide 20 mcg (Forteo, Lilly; 6.2%, P=.0139) or denosumab 60 mg (Prolia, Amgen; 5.5%, P=.0005) monotherapy groups, researchers wrote. In addition, higher increases in femoral-neck BMD were observed in the combination group (4.2%) vs. teriparatide (0.8%; P=.0007) and denosumab (2.1%; P=.0238) alone. This also was true for total-hip BMD (combination: 4.9%; teriparatide: 0.7%, P<.0001; denosumab: 2.5%, P=.0011).
Postmenopausal women (n=94) aged at least 45 years with osteoporosis were randomly assigned teriparatide injection daily (n=31), denosumab every 6 months (n=33) or a combination of the two treatments (n=30). Researchers measured BMD at baseline, 3, 6 and 12 months.
“Our results demonstrate that the combination of denosumab and teriparatide increases bone density more than either individual therapy, most likely because denosumab is able to potently block bone resorption even when given along with a bone-building agent like teriparatide,” study researcher Benjamin Z. Leder, MD, of Massachusetts General Hospital, said in a press release. “While additional studies are needed, the results suggest that this combination may prove to be an effective osteoporosis treatment in women at especially high risk of fracture.”
In an accompanying editorial, Richard Eastell, MD, FRCP, FRCPI, FRCPEdin, professor and head of the academic unit of bone metabolism and director of the Mellanby Centre for bone research at the University of Sheffield in the United Kingdom, and Jennifer S. Walsh, PhD, also of the Mellanby Centre for bone research, wrote that Tsai and colleagues found proof of concept for the additive effects of these combined therapies compared with the agents alone.
“Whether the combination remains effective needs to be investigated, however, because at 12 months mean concentrations of the bone formation marker PINP no longer differed between the denosumab-alone and combination-therapy groups,” Eastell and Walsh wrote.
They also suggest further studies on the safety of this combination and a cost-effectiveness assessment on the risk for fracture.
For more information:
Eastell R. Lancet. 2013;doi:10.1016/S0140-6736(13)60984-8.
Tsai JN. Lancet. 2013;doi:10.1016/S0140-6736(13)60856-9.
Disclosure: All study researchers report research funding from Amgen and Eli Lilly. Eastell reports consultancy for and research funding from Amgen, GlaxoSmithKline, Lilly, Merck and Novartis. Walsh reports no relevant financial disclosures.
Perspective
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Donald A. Bergman, MD
This paper shows that the RANK ligand inhibitor, denosumab, when combined with the anabolic agent teriparatide, increased bone density in spine and hip better than either agent alone. Bone density was measured at 0, 3, 6 and 12 months. The authors suggest that when these two drugs are used together, there may be an uncoupling of bone formation and resorption (leading to persistent suppression of resorption by denosumab) accounting for the better results than were found when teriparatide was combined with a bisphosphonate (bone resorption was not inhibited as much as when the bisphosphosphonate was used.
Although these results sound promising, there are concerns. This was a relatively short study, and there most likely will not be an ongoing increase in density over the long term. The potentially harmful consequences to bone of a powerful suppressive agent like denosumab, even when used with an anabolic agent, were not addressed by this short study. Also, as the authors themselves point out, this study did not evaluate fracture risk reduction. Although increasing bone density usually means reduced risk of fracture that is not always the case. For example, fluoride increases density of bone but increases fracture risk possibly because of abnormal mineral crystal size. Teriparatide when used alone may result in a decrease in hip density, and yet fracture risk is reduced.
Longer studies looking at fracture risk reduction at all sites (spine, hip and extremities) are needed.
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